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In neurons calcium plays a dual role as a charge carrier and an intracellular messenger. Calcium signals regulate various developmental processes and have a key role in apoptosis, neurotransmitter release and membrane excitability. How can one ubiquitous intracellular messenger regulate so many different vital processes in parallel, but also work independently? The answer lies in the versatility of the calcium signaling mechanisms in terms of amplitude and spatiotemporal patterning within a neuron. Here we describe some of the main contributors to neuronal calcium signaling.
Voltage-gated calcium channels are the primary mediators of depolarization-induced calcium entry into neurons. There is great diversity in calcium channel subtypes due to multiple genes that encode calcium channel subunits, alternative splicing and coassembly with a variety of ancillary calcium channel subunits. This allows VGCCs to carry out distinct roles in specific neuronal subtypes and at particular subcellular loci.
Under resting conditions, intracellular calcium concentrations lie in the 100 nM range due to calcium-buffering molecules and sequestration into intracellular calcium stores. VGCCs opening result in calcium influx along the electrochemical gradient, leading to a transient, localized elevation of intracellular calcium concentration into the high micromolar range. This in turn triggers a wide range of calcium-dependent processes that include gene transcription, neurotransmitter release, neurite outgrowth, and the activation of calcium-dependent enzymes such as calmodulin-dependent protein kinase II and protein kinase C.
Calcium storage is one of the functions commonly attributed to the endoplasmic reticulum (ER) through calcium release channels inositol trisphosphate receptors (IP3Rs) and ryanodine receptors (RyRs). Calcium signals resulting from calcium release from internal stores have been found in various types of neurons at different developmental stages. While IP3-mediated calcium release is mostly triggered by neurotransmitters such as glutamate (see below), RyRs can be activated by elevations of the cytosolic calcium concentration. This calcium-induced calcium release mediated by RyR can contribute to the amplification of the calcium influx generated by action potential firing in neurons. Both IP3Rs and RyRs are regulated by calcium itself along with other intracellular factors. This dependence on calcium establishes a feedback loop coordinating calcium influx from the internal stores into the cytosol. In the case of IP3Rs, calcium influx plays an essential role for in generating calcium waves in neocortical and other types of neurons.
NMDA receptors are ionotropic glutamate receptors and mediate a major part of the postsynaptic calcium influx in the dendritic spines of various neuronal cell types and cortex. This rise in spinal calcium concentration is particularly important for the long-term modification of synaptic strength. NMDA receptor channels are nonspecific cation channels that are permeable for sodium, potassium, and calcium ions.
Calcium-permeable AMPA receptors are another class of ionotropic glutamate receptors. They are found in many forms of aspiny GABAergic neurons and are characterized by the lack of a GluR2 receptor subunit. GluR2-lacking AMPA receptors are permeable for sodium, calcium, potassium and zinc ions. Calcium-permeable AMPA receptors have a high conductance in response to tetanic stimulation and enables individual neurons to produce different types of responses to distinct synaptic inputs. Importantly, the presence of GluR2-containing (native AMPA receptors) and GluR2-lacking AMPA receptors (calcium-permeable AMPA receptors) is not static, but is highly regulated, particularly in response to neuronal activity. Thus, permeability of AMPA receptors to calcium is dynamic within a given neuron and can therefore contribute to synaptic plasticity mechanisms in aspiny neurons.
Direct calcium entry through AMPA receptors is capable of triggering neuronal death. Therefore the divergence in relative calcium permeability of AMPA receptors between different neuronal cell types could be an important determinant of selective neuronal vulnerability.
mGluRs are 7-transmembrane G protein-coupled receptors that are broadly distributed within the central and peripheral nervous sytems. They are classified in group I, II, and III mGluRs, are expressed in a cell-type-specific fashion, and exert diverse physiological roles. The receptor classes differ in their downstream signaling mechanisms; for example, mGluR1 are coupled to the Gq protein. In expression systems, the mGluR1 subtype of this group mediates both an increase in intracellular calcium as well as a TRPC3-dependent inward current. Upon activation of mGluR1, phospholipase C mediates the generation of IP3, which binds to receptors in the ER and induces calcium release. In contrast, an activation of native mGluR5 in neurons induces different cellular effects. In hippocampal neurons, mGluR5 elicits a single peaked intracellular calcium response, whereas in the neocortex it induces intracellular calcium oscillations.
The major challenge in the analysis of the various sources of neuronal calcium signaling is that they are generally not active one at a time, but have overlapping activities with strong interactions. Therefore, calcium imaging is invaluable for decoding the specific signaling mechanisms in neurons.